The House of Medici was a prominent family in the Italian city of Florence during the late 15th century. Lorenzo de' Medici was the head of the house, and a close ally of the Auditore family, and their Assassin connections. Due to their de facto control of Florence during this period, they were subject to a major Templar attack.

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The Medici family came from the agricultural Mugello region, north of Florence, being mentioned for the first time in 1230. The origin of the name Medici is uncertain, although Medici is the plural for Medico, a doctor.

Throughout a great part of the 15th century, Cosimo de' Medici, followed by Piero de' Medici, and lastly Lorenzo de' Medici ruled over Florence. Cosimo Medici, whose power stemmed from his vast wealth, ruled over Florence until his death in 1464, when he was succeeded by his son, Piero.

Piero's reign was short, spanning only five years before he succumbed to gout. After Piero, Lorenzo became the head of the Medici family. Like his grandfather and father, Lorenzo ruled Florence, through surrogates in the city councils, threats, payoffs, and strategic marriages. The Medici under Lorenzo were great patrons of arts and culture, and with his rule, Florence became the center of culture and innovation.

In 1478, while attending High Mass, Lorenzo and his brother, Giuliano, were attacked by members of the Pazzi family and their allies, in an event that would later be known as the Pazzi Conspiracy. Although the conspirators managed to kill Giuliano, Lorenzo was saved by Ezio Auditore, who then returned Lorenzo to his home. Once there, Lorenzo instructed Ezio to kill the main conspirator, Francesco de' Pazzi. After Ezio assassinated Francesco, he met with Lorenzo at the Ponte Vecchio. Once there, Lorenzo gifted Ezio a codex page as well as the names of Francesco's co-conspirators. After the meeting, Ezio left for Tuscany to pursue those responsible for the conspiracy.

Once Ezio had killed all those who played a part in the conspiracy, he returned to Lorenzo, who then presented him with the Medici cape as a symbol of faith and trust, and the two parted ways.

After Lorenzo's death in 1492, his son Piero took control of the house. Unfortunately, Piero let Florence fall into the hands of Girolamo Savonarola, who bewitched the citizens with a Piece of Eden.

Ezio Auditore returned to Florence in 1497, only to find that Savonarola had taken control over the city from the Medici. Finally in 1498, Ezio assassinated Savonarola and allowed the Medici to try and regain power. Despite this, it took the Medici fourteen years to regain control of Florence.